Visna is a naturally occurring chronic neurological disease of sheep caused by a persistent infection with a retravirus. An experimental model has been established in Icelandic sheep, and we are conducting an ongoing study of the pathogenesis of this classical slow infection. These studies have established that (a) The infection is widespread but very few cells are infected, only minimal levels of free infectious virus are released, and infection is often limited to latently infected cells. (b) Antibody is raised only slowly, appearing in serum at 1-3 months as measured by CF and N tests. (c) Brain lesions evolve quite rapidly for the first month after infection but then become stabilized, with very irregular exacerbations and highly variable incubation periods. (d) The lesions can be prevented by ALS immunosuppression and are probably mediated by a cellular response to virus-specified antigens. (e) There are a number of antigenic variants of the virus, distinguishable in the N test, and serological studies suggest that, following infection with a single serotype, other variants may appear at irregular intervals. Work now proposed is focused primarily on (1) description of antigenic drift during longterm infection by characterizing serial isolates and N antibody specificity using specimens already collected. (2) study of spinal fluids to determine the levels of specific classes of immunoglobulin, the titers of class-specific antiviral antibody, the frequency and specificity of oligoclonal immunoglobulin, and the presence of basic protein or its antibody. (3) a description of cellular immune response in blood, efferent lymph, and CSF, using virus-specific lymphocyte blast transformation. (4) correlation of these parameters with the tempo of evolving CNS lesions, to explain the determinants which control progression of this chronic neurological disease.